The NCCTG Neuro-Oncology Program consists of three components: Cancer Treatment Trials, Neurobehavioral Studies, and Laboratory Correlates. These complementary components contribute to improving duration and quality of life in patients with primary central nervous system malignancies and to enhancing our understanding of the underlying disease process. During the previous grant cycle, in low-grade glioma patients, we observed that 65 cGy radiation is not better than 50 cGy; pro-carbazine, CCNU, grade glioma patients, we observed that 65 cGy radiation is not better than 50 cGy; procarbazine, CCNU, and vincristine (PCV) is an active regimen as initial therapy; and deletions in chromosomes 1p and 19q are associated with the diagnosis of low-grade oligodendrogliona, but not with low-grade oligoastrocytoma. In patients with high-grade glioma (glioblastoma multiforme, anaplastic oligoastrocytoma), we demonstrated that recombinant alpha interferon does not improve survival when added to radiation and BCNU, but is considerably more toxic; than grading (grade 3 versus grade 4) has significant prognostic value in patients with anaplastic oligoastrocytoma; and that, grade for grade, patients with anaplastic oligoastrocytoma have a statistically significant improved survival compared to those with pure astrocytoma. Moreover, tumoral EGFR amplification, absence of p53 mutations, and PTEN deletions are associated with poor survival in anaplastic astrocytoma patients. Glioblastoma and gliosarcoma patients have essentially identical clinical courses and genetic abnormalities. In recurrent glioma patients, we identified two active regimens: MOP (nitrogen mustard, vincristine, and procarbazine) and irinotecan. Ph. Pharmacokinetic studies demonstrated increase in CPT-11 clearance and variable metabolism in patients receiving irinotecal and anti-convulsants concurrently. Non-glioblastoma patients were more likely to respond to treatment than those with recurrent glioblastoma. Neurobehavioral studies indicated that good baseline Folstein and Folstein mini-mental status examination (MMSE) score is associated with better survival on multi-variate analyses. Few patients with high-grade glioma had diminished mini-mental examination scores at one year and 18 months in the absence of tumor progression. Conversely, reduction in mini-mental status examination scores correlated strongly with both at diagnosis, and were more likely to have cognitive decline to have cognitive decline as a consequence of treatment compared with younger patients. In patients with primary CNS lymphoma, we found a high response rate with CHOP (cyclophosphamide, doxorubicin, vincristine, and dexamethasone), but the duration of benefit was very short. As in patients with high-grade glioma, MMSE scores declined in close association with tumor progression. Future plans include continued evaluation of agents with radiosensitizing properties including cisplatin and irinotecan. We will continue to evaluate the efficacy of new regimens in recurrent glioma patients, including pyrazoloacridine plus carboplatin and the rapamycin analog, CCI 779. NCCTG has recruited investigators demonstrating experience with inhibitors of tumor invasion, as well as gene therapy. There are two main gene therapy approaches current in preclinical investigation: fusogenic membrane glycoproteins such as the measles virus F and H proteins and the truncated Gibbon Ape Leukemia virus surface protein (GALV). Neurobehavioral studies, including evaluation and treatment of impaired cognitive status, depression, fatigue, and excessive daytime somnolence, are in process. Pharmacokinetic studies to investigate interactions among chemotherapeutic agents and anti-convulsants will continue. Studies of genetic alterations in glioma, especially anaplastic astrocytoma and low- grade glioma, will be expanded through collaborations with Drs. Robert Jenkins (Mayo) David James (Mayo), and Bert Feuerstein (UCSF).